| Tetramethylphenylenediamine protects the isolated heart against ischaemia-induced apoptosis and reperfusion-induced necrosis. | |
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MedLine Citation:
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PMID: 21077848 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Cytochrome c when released from mitochondria into cytosol triggers assembly of the apoptosome resulting in caspase activation. Recent evidence suggests that reduced cytochrome c is unable to activate the caspase cascade. In this study, we investigated whether a chemical reductant of cytochrome c, N,N,N',N'-tetramethylphenylene-1,4-diamine (TMPD), which we have previously shown to block cytochrome c-induced caspase activation, could prevent ischaemia-induced apoptosis in the rat perfused heart. EXPERIMENTAL APPROACH: The Langendorff-perfused rat hearts were pretreated with TMPD and subjected to stop-flow ischaemia or ischaemia/reperfusion. The activation of caspases (measured as DEVD-p-nitroanilide-cleaving activity), nuclear apoptosis of cardiomyocytes (measured by dUTP nick end labelling assay), mitochondrial and cytosolic levels of cytochrome c (measured spectrophotometrically and by elisa), and reperfusion-induced necrosis (measured as the activity of creatine kinase released into perfusate) were assessed. KEY RESULTS: We found that perfusion of the hearts with TMPD strongly inhibited ischaemia- or ischaemia/reperfusion-induced activation of caspases and partially prevented nuclear apoptosis in cardiomyocytes. TMPD did not prevent ischaemia- or ischaemia/reperfusion-induced release of cytochrome c from mitochondria into cytosol. TMPD also inhibited ischaemia/reperfusion-induced necrosis. CONCLUSIONS AND IMPLICATIONS: These results suggest that TMPD or related molecules might be used to protect the heart against damage induced by ischaemia/reperfusion. The mechanism of this protective effect of TMPD probably involves electron reduction of cytochrome c (without decreasing its release) which then inhibits the activation of caspases. |
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Authors:
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Jurgita Barauskaite; Regina Grybauskiene; Ramune Morkuniene; Vilmante Borutaite; Guy C Brown |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 162 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-01-28 Completed Date: 2011-05-06 Revised Date: 2012-09-24 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1136-42 Citation Subset: IM |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Institute for Biomedical Research, Lithuanian University of Health Sciences, Kaunas, Lithuania. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Cardiotonic Agents / pharmacology* Caspases / metabolism Cytochromes c / metabolism Cytosol / metabolism Enzyme Activation / drug effects Male Mitochondria, Heart / drug effects, metabolism Myocardial Reperfusion Injury / metabolism, pathology, prevention & control* Necrosis / prevention & control Rats Rats, Wistar Tetramethylphenylenediamine / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 27215-51-6/Tetramethylphenylenediamine; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
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